Protein drugs typified by biomedicines, plasma derivatives, and the like have raised concerns about contamination by ingredient-derived or process-derived viruses. Thus, when such protein drugs are manufactured, the inactivation or removal of viruses in the drugs is very important from the viewpoint of the safety and stability of the drugs. This inactivation of viruses has been practiced by a method such as heat treatment or treatment with chemical agents. These treatments, however, are not sufficient in themselves for the inactivation of viruses. In addition, these methods might denature the proteins themselves in the drugs. Against this backdrop, the viruses are separated and removed by filtration using virus removal membranes as physical virus removal means without chemical denaturation (e.g., Patent Literatures 1 to 3).
Virus removal membranes made of natural materials such as cellulose or of synthetic polymer materials such as polyvinylidene fluoride (PVDF) or polyether sulfone (PES) are known (Non Patent Literatures 1 to 4). Particularly, in the case of protein solutions containing small protein molecules, small-pore size virus removal membranes having a pore size that does not permit permeation of viruses but permits permeation of the protein molecules are used.
Ideally, the filtration of virus-containing solutions using a virus removal apparatus equipped with a virus removal membrane should filter larger amounts of protein solutions in a short time and should exert sufficiently high virus removal performance. To treat larger amounts of protein solutions in a short time, filtration of virus-containing solutions is generally carried out at a pressure as high as possible. However, the continuation of such high-pressure filtration may leave inside the membrane, proteins supposed to be contained in filtrates. In addition, recent protein drugs tend to have higher concentrations of proteins. Along with this tendency, there is also a growing demand for higher protein concentrations in the filtration step for removing viruses. In the case of filtering high-concentration protein solutions through a small-pore size virus removal membrane, clogging frequently occurs, particularly, due to proteins remaining inside the membrane.
Such proteins remaining inside the small-pore size virus removal membrane are recovered by filtration with a protein-free buffer solution (usually, the same as a buffer solution used for dissolving the proteins) as a washing solution. This filtration step is added after the protein filtration and therefore called post-wash or post-filtration. For this post-wash, typically, the filtration pressure is temporarily relieved in order to have a switching, at an entrance of solution to be filtered, from a line for protein solutions to a line for washing solutions. If the filtration pressure is not decreased, the solution flows backward to the washing solution side.
Examples of such decrease in filtration pressure during filtration through a virus removal membrane, as in the post-wash step, include a case in which pressurization is suspended during filtration for a reason such as a power failure (this case is called stop and start).
Depending on the types of protein drugs, low filtration pressures may be desirable for filtration through a virus removal membrane during manufacturing of the drugs. Such filtration at low filtration pressures is often carried out in order to increase the final throughputs of solutions that tend to cause clogging or in order to increase the rate of permeation or recovery of solutions of high-molecular proteins in elongated shapes. When low filtration pressures are adopted, specific filtration pressures are often determined to balance permeability and productivity and also depend on the concentrations, etc. of the protein drugs to be obtained. For example, Patent Literature 4 has adopted a filtration pressure on the order of 0.15 kgf/cm2.